The present invention relates to a class of pyrazine compounds which are useful in the treatment of central nervous system (CNS) diseases and disorders and to their pharmaceutically acceptable derivatives, pharmaceutical compositions containing them, to their use in the treatment of such disorders and to methods of preparing them.
Numerous phenyl pyrazine derivatives are known in the prior art. For example, Synthesis (1987), (10), 914-915, describes phenyl pyrazine derivatives including, inter alia, 3-(4-chlorophenyl)-pyrazinamine. No pharmaceutical utility is however described in that prior art document.
The present invention relates to a series of pyrazine derivatives which are sodium channel blockers. These compounds are particularly good anti-convulsants and as such are useful in the treatment of CNS diseases such as epilepsy.
Accordingly, the invention provides a compound of formula (I) 
wherein
R1 is selected from the group consisting of phenyl substituted by one or more halogen atoms, naphthyl and naphthyl substituted by one or more halogen atoms;
R2 is selected from the group consisting of xe2x80x94NH2 and xe2x80x94NHC((xe2x95x90O))Ra;
R3 is selected from the group consisting of xe2x80x94NRbRc, xe2x80x94NHC((xe2x95x90O))Ra and hydrogen;
R4 is selected from the group consisting of hydrogen, xe2x80x94C1-4 alkyl (preferably methyl), xe2x80x94C1-4 alkyl (preferably methyl) substituted by one or more halogen atoms, xe2x80x94CN, xe2x80x94CH2OH, xe2x80x94CH2OR and xe2x80x94CH2S(O)xRd;
wherein
Ra represents C1-4 alkyl or C3-7cycloalkyl, and
Rb and Rc, which may be the same or different, are selected from hydrogen and C1-4 alkyl, or together with the nitrogen atom to which they are attached, form a 6-membered nitrogen containing heterocycle, which heterocycle can be further substituted with one or more C1-4 alkyl;
Rd is selected from C1-4 alkyl or C1-4 alkyl substituted by one or more halogen atoms;
x is an integer zero, one or two;
and pharmaceutically acceptable derivatives thereof;
with the proviso that R1 does not represent; 
when R2 is xe2x80x94NH2, and both R3 and R4 are hydrogen.
By pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt or solvate of the compounds of formula (I), or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof (eg. a prodrug). Reference hereinafter to the compounds of formula (I) includes the compound of formula (I) and pharmaceutically acceptable derivatives thereof.
Suitable prodrugs are well-known in the art and include N-acyl derivatives, for example at any of the nitrogens in the compounds of formula (I), for example simple acyl derivatives such as acetyl, propionyl and the like or groups such as Rxe2x80x94Oxe2x80x94CH2-nitrogen or Rxe2x80x94Oxe2x80x94C(O)-nitrogen.
As used herein, the term halogen atom includes fluorine, chlorine, bromine or iodine.
The term C1-4alkyl as used herein includes straight chained and branched alkyl groups containing 1 to 4 carbon atoms, and in particular includes methyl and isopropyl.
The term C3-7cycloalkyl includes groups containing 3 to 7 carbon atoms, and in particular includes cyclopropyl.
The term heterocycle as used herein includes 6 membered heterocycles containing at least one nitrogen heteroatom, and preferably two nitrogen heteroatoms. A particularly suitable heterocycle is piperazinyl.
R1 is aptly selected from unsubstituted naphthyl and phenyl substituted by one or more halogen atoms. Particularly R1 represents phenyl substituted by more than one halogen atom, such as di- or tri-halogenated phenyl. Preferably, the halogen substituent in R1 is chloro. Suitably R1 is selected from 2,3,5-trichlorophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 1-naphthyl and 2-naphthyl. In particular, R1 is 2,3,5-trichlorophenyl.
Suitably R2 is selected from xe2x80x94NH2, isopropylcarbonylamino and cyclopropylcarbonylamino. R2 is preferably xe2x80x94NH2.
Suitably R3 is selected from hydrogen, xe2x80x94NH2, dimethylamino, 4-methyl-1-piperazinyl, acetamido, isopropylcarbonylamino, cyclopropylcarbonylamino. R3 is preferably xe2x80x94NH2.
Suitably R4 is selected from hydrogen, xe2x80x94CN, xe2x80x94CH2OH or methyl. R4 is preferably xe2x80x94CH2OH or, more preferably, hydrogen.
More preferably, R2 and R3 are both xe2x80x94NH2.
A preferred class of compounds of formula (I) includes those wherein R1, R2 and R3 are as defined above and R4 is selected from the group consisting of hydrogen, xe2x80x94C1-4 alkyl (preferably methyl) and xe2x80x94C1-4 alkyl (preferably methyl) substituted by one or more halogen atoms.
A preferred compound of formula (I) is wherein
R1 is 2,3,5-trichlorophenyl; R2 is xe2x80x94NH2; R3 is xe2x80x94NH2; and R4 is hydrogen.
According to a particular embodiment of the present invention, there is provided a compound of formula (Ia) 
wherein
Hal represents a halogen atom selected from fluorine, chlorine, bromine and iodine;
n is 2 or 3;
R2 is selected from the group consisting of xe2x80x94NH2 and xe2x80x94NHC((xe2x95x90O))Ra;
R3 is selected from the group consisting of xe2x80x94NRbRc, xe2x80x94NHC((xe2x95x90O))Ra and hydrogen;
R4 is selected from the group consisting of hydrogen, xe2x80x94C1-4 alkyl (preferably methyl), xe2x80x94C1-4 alkyl (preferably methyl) substituted by one or more halogen atoms, xe2x80x94CN, xe2x80x94CH2OH, CH2ORd and xe2x80x94CH2S(O)xRd;
wherein
Ra represents C1-4 alkyl or C3-7cycloalkyl, and
Rb and Rc, which may be the same or different, are selected from hydrogen and C1-4 alkyl, or together with the nitrogen atom to which they are attached, form a 6-membered nitrogen containing heterocycle, which heterocycle can be further substituted with one or more C1-4 alkyl;
Rd is selected from C1-4 alkyl or C1-4 alkyl substituted by one or more halogen atoms;
x is an integer zero, one or two;
and pharmaceutically acceptable derivatives thereof.
It will be appreciated that R2, R3 and R4 as defined above for formula (Ia), are substantially as hereinbefore described with reference to formula (I).
Particuarly appropriately in formula (Ia), R2 and R3 both represent xe2x80x94NH2. Aptly R4 represents xe2x80x94CN, methyl or, more appropriately, xe2x80x94CH2OH or, even more appropriately, hydrogen.
Aptly Hal in formula (Ia) represents chlorine. Suitably n is 3, and appropriately the resulting tri-substitution represents a compound of the following formula (Ib) 
wherein R2, R3 and R4 are substantially as defined above with reference to formula (Ia);
and pharmaceutically acceptable derivatives thereof.
Preferred compounds of the present invention are
2,6-diamino-3-(2,3-dichlorophenyl)pyrazine,
2,6-diamino-3-(2,5-dichlorophenyl)pyrazine,
2,6-diamino-3-(1-naphthyl)pyrazine,
2,6-diamino-3-(2-naphthyl)pyrazine,
2-amino-6-(4-methyl-piperazinyl)-3-(2,3,5-trichlorophenyl)pyrazine,
2-amino-6-dimethylamino-3-(2,3-dichlorophenyl)pyrazine,
2-amino-6-dimethylamino-3-(1-naphthyl)pyrazine,
2,6-dicyclopropylcarbonylamino-3-(2,3,5-trichlorophenyl)pyrazine,
2-amino-6-cyclopropylcarbonylamino-3-(2,3,5-trichlorophenyl)pyrazine,
2,6-diisopropylcarbonylamino-3-(2,3,5-trichlorophenyl)pyrazine,
2-amino-6-isopropylcarbonylamino-3-(2,3,5-trichlorophenyl)pyrazine,
2-isopropylcarbonylamino-6-amino-3-(2,3,5-trichlorophenyl)pyrazine,
2-cyclopropylcarbonylamino-6-amino-3-(2,3,5-trichlorophenyl)pyrazine,
2-amino-6-acetamido-3-(2,3,5-trichlorophenyl)pyrazine,
2-amino-6-acetamido-3-(2,5-dichlorophenyl)pyrazine,
2-amino-6-acetamido-3-(2-naphthalene)pyrazine,
5-methyl-2,6-Diamino-3-(2,3,5-trichlorophenyl)pyrazine,
5-cyano-2,6-Diamino-3-(2,3,5-trichlorophenyl)pyrazine,
and pharmaceutically acceptable derivatives thereof.
Further preferred is the compound 5-hydroxymethyl-2,6-diamino-3-(2,3,5-trichlorophenyl)pyrazine and pharmaceutically acceptable derivatives thereof.
A particularly preferred compound according to the present invention is 2,6-diamino-3-(2,3,5-trichlorophenyl)pyrazine and pharmaceutically acceptable derivatives thereof.
It is to be understood that the present invention covers all combinations of particular and preferred groups described herein above.
The compounds of formula (I) are particularly useful as anticonvulsants. They are therefore useful in treating epilepsy. They may be used to improve the condition of a host, typically a human being, suffering from epilepsy. They may be employed to alleviate the symptoms of epilepsy in a host. xe2x80x9cEpilepsyxe2x80x9d is intended to include the following seizures:xe2x80x94simple partial seizures, complex partial seizures, secondary generalised seizures, generalised seizures including absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic clonic seizures and atonic seizures.
The compounds of formula (I) are additionally useful in the treatment of bipolar disorder, alternatively known as manic depression. Type I or II bipolar disorder may be treated. The compounds of formula (I) may thus be used to improve the condition of a human patient suffering from bipolar disorder. They may be used to alleviate the symptoms of bipolar disorder in a host. The compounds of formula (I) may also be used in the treatment of unipolar depression.
The compounds of formula (I) are useful as analgesics. They are therefore useful in treating or preventing pain. They may be used to improve the condition of a host, typically a human being, suffering from pain. They may be employed to alleviate pain in a host. Thus, the compounds of formula (I) may be used as a preemptive analgesic to treat acute pain such as musculoskeletal pain, post operative pain and surgical pain, chronic pain such as chronic inflammatory pain (e.g. rheumatoid arthritis and osteoarthritis), neuropathic pain (e.g. post herpetic neuralgia, trigeminal neuralgia and sympathetically maintained pain) and pain associated with cancer and fibromyalgia. The compounds of formula (I) may also be used in the treatment or prevention of pain associated with migraine.
The compounds of formula (I) are further useful in the treatment of functional bowel disorders which include non-ulcer dyspepsia, non-cardiac chest pain and in particular irritable bowel syndrome. Irritable bowel syndrome is a gastrointestinal disorder characterised by the presence of abdominal pain and altered bowel habits without any evidence of organic disease. The compounds of formula (I) may thus be used to alleviate pain associated with irritable bowel syndrome. The condition of a human patient suffering from irritable bowel syndrome may thus be improved.
The compounds of formula (I) may also be useful in the treatment of neurodegenerative diseases, such as Alzheimer""s disease, ALS, motor neuron disease and Parkinson""s disease. The compounds of formula (I) may also be useful in neuroprotection and in the treatment of neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury or the like.
Still further, the compounds of formula (I) are also useful in preventing or reducing dependence on, or preventing or reducing tolerance or reverse tolerance to, a dependencexe2x80x94inducing agent. Examples of dependence inducing agents include opioids (eg morphine), CNS depressants (eg ethanol), psychostimulants (eg cocaine) and nicotine.
There is therefore further provided by the present invention, use of a compound of formula (I) in the manufacture of a medicament for use in the treatment of a disorder substantially as hereinbefore described. The present invention further comprises a method of treating a patient suffering from, or susceptible to, a disorder substantially as hereinbefore described, which method comprises administering to the patient a therapeutically effective amount of a compound of formula (I). The term xe2x80x9ctreatmentxe2x80x9d as used herein includes the treatment of established disorders, and also includes the prophylaxis thereof.
Compounds according to the invention are particularly useful in the treatment of epilepsy and bipolar disorder, especially epilepsy.
The precise amount of the compound of formula (I) or salt thereof administered to a host, particularly a human patient, will be the responsibility of the attendant physician. However, the dose employed will depend upon a number of factors including the age and sex of the patient, the precise condition being treated and its severity, and the route of administration.
The compound of formula (I) and its salts may be administered at a dose of from 0.1 to 10 mg/kg body weight per day and more particularly 0.5 to 5 mg/kg body weight per day, calculated as the free base. The dose range for adult human beings is generally from 5 to 1000 mg/day, such as from 5 to 200 mg/day, preferably from 10 to 50 mg/day, calculated as the free base.
While it is possible for the compound of formula (I) or a pharmaceutically acceptable derivative thereof to be administered as the raw chemical, it is preferable to present it as a pharmaceutical formulation. The formulations of the present invention comprise the compound of formula (I) or a pharmaceutically acceptable derivative thereof together with one or more acceptable carriers or diluents therefor and optionally other therapeutic ingredients. The carrier(s) must be xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The formulations include those suitable for oral, parenteral (including subcutaneous e.g. by injection or by depot tablet, intradermal, intrathecal, intramuscular e.g. by depot and intravenous), rectal and topical (including dermal, buccal and sublingual) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof (xe2x80x9cactive ingredientxe2x80x9d) with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets (e.g. chewable tablets in particular for paediatric administration) each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of a sterile liquid carrier, for example, water-for-injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter, hard fat or polyethylene glycol.
Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
The compounds of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
In addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
Preferred unit dosage formulations are those containing an effective daily dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient. Conveniently that may be from 5 mg to 1000 mg, more conveniently from 5 mg to 200 mg (eg. 5, 25 and 100 mg) and most conveniently 10 mg to 50 mg, calculated as the free base.
When compounds of formula (I) are used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route.
Compounds of formula (I) (which does of course also include compounds of formula (Ia) and (Ib)) and pharmaceutically acceptable salts and solvates thereof may be prepared by methods known in the art for the preparation of analogous examples. In particular, the compounds of formula (I) may be prepared by the methods outlined below and which form a further aspect of the invention. In the following processes R1, R2, R3 and R4, unless otherwise specified are as defined herein above for formula (I).
According to a general process (A), a compound of formula (I) may be prepared under suitable reaction conditions from a compound of formula (II) 
where Hal (B) represents a halogen atom, suitably chloride. For example, Hal(B) may be converted to xe2x80x94NRbRc by reaction with an appropriate amine in a solvent, such as ethanol.
A compound of formula (II) may suitably be prepared from a compound of formula (III) 
by reaction with a compound of formula (IV) R1B(OH)2. Examples of compounds of formula (IV) R1B(OH)2 include 2,3,5-trichlorobenzeneboronic acid, 2,3-dichlorobenzeneboronic acid, 2,5-dichlorobenzeneboronic acid, 1-naphthaleneboronic acid and 2-naphthaleneboronic acid. Appropriately, Hal(A) in above formula (III) is more reactive than Hal(B), and suitably Hal(A) is selected from bromide and iodide, whereas Hal(B) is aptly chloride. Compounds of formula (IV) are either commercially available or can suitably be prepared from commercially available benzene analogues e.g. 1-bromo-2,3-dichlorobenzene or 2-bromo-4,6-dichloroaniline as described herein after in greater detail in the accompanying Examples.
A compound of formula (III) can be suitably prepared by further halogenating a compound of formula (V) 
for example by reaction with a halogenating agent, such as N-bromosuccinimide, with stirring at room temperature for several hours.
A compound of formula (V) can be prepared from a di-halo compound of formula (VI) 
by reaction with R2H, where Hal(B) and Hal(C), which may be the same or different halogen substituents. Aptly both Hal(B) and Hal(C) are chloride. Compounds of formula (VI) are commercially available.
According to a further general process (B), a compound of formula (I) can be prepared from a compound of formula (VII) 
where Hal represents a halogen atom, suitably bromide or iodide, by reaction with a compound of formula (IV) as described above.
In the case where both R3 and R4 represent hydrogen, a compound of formula (VII) may be commercially available. Alternatively, a compound of formula (VII) can be prepared from a compound of formula (VIII) 
where Y is a group easily convertable to R3. For example, in the case where Y represents NH2, this can be converted to xe2x80x94NHC((xe2x95x90O))CH3 by reflux in the presence of an acetylating agent, such as acetic anhydride.
A compound of formula (VIII) can be prepared from a compound of formula (IX) 
by reaction with R2H under suitable conditions. For example a compound of formula (IX) can be reacted with ammonia in an autoclave for several hours.
A compound of formula (IX) can be prepared from a compound of formula (X) 
which in turn can be prepared from commercially available compounds of formula (VI) described above.
According to a further process, C, compounds of formula (I) where R2 represents NH2 may be prepared by cylisation and oxidation of a compound of formula (XI) 
or a salt thereof according to conventional procedures, for example by neutralising a salt of a compound of formula (XI), e.g. with lithium hydroxide in a suitable solvent such as an alcohol, e.g. methanol, under which conditions spontaneous oxidation to a compound of formula (I) occurs.
Compounds of formula (XI) may be prepared by reacting compounds of formula (XII) R1C(O)H with compounds of formula (XIII) 
or a salt thereof, in the presence of a cyanide source, for example potassium cyanide. Compounds of formula (XII), where R1 is trihalo-substituted phenyl, for example 2,3,5-trichlorobenzaldehyde, are known and may be prepared according to the methods described in WO95/07877. Compounds where R1 represents alternative values are either known or may be prepared according to methods known for the preparation of known compounds.
Compounds of formula (XIII), for example aminoacetamidine, may be prepared according to known procedures, for example, those described in Chem. Berichte, 89, 1185 (1956).
According to a further process, D, compounds of formula (I) may be converted into corresponding compounds of formula (I) by employing suitable reaction techniques. For example, compounds of formula (I) wherein R3 represents xe2x80x94NHC((xe2x95x90O))Ra may be converted into compounds wherein R3 represents xe2x80x94NH2 by hydrolysis, for example by reaction with aqueous hydrochloric acid. In addition, compounds of formula (I) wherein R4 represents hydrogen may be converted into compounds where R4 represents xe2x80x94CN by first halogenating by reacting with a halogenating agent, such as N-bromosuccinimide, followed by reaction with a suitable source of cyanide ions, for example a mixture of sodium cyanide and copper (I) cyanide. Further, compounds of formula (I) wherein R4 represents CN may be converted into compounds wherein R4 represents xe2x80x94CH2OH via the formyl derivative which may be prepared by reacting the xe2x80x94CN compound with diisobutylaluminium hydride in toluene, followed by hydrolysis. The formyl derivative is then reduced to the xe2x80x94CH2OH compound using, for example, sodium borohydride in ethanol. Compounds wherein R4 represents xe2x80x94CH2OH may be converted into compounds wherein R4 represents xe2x80x94CH2ORd by alkylation. In addition, of formula (I) wherein R4 represents xe2x80x94CN may be converted into compounds wherein R4 represents methyl via the formyl derivative, prepared as desribed above, which is then converted into the tosylhydrazone, by reaction with p-toluenesulfonhydrazide, followed by reaction with catecholborane in chloroform/tetrahydrofuran.
The various general methods described above may be useful for the introduction of the desired groups at any stage in the stepwise formation of the required compound, and it will be appreciated that these general methods can be combined in different ways in such multi-stage processes. The sequence of the reactions in multi-stage processes should of course be chosen so that the reaction conditions used do not affect groups in the molecule which are desired in the final product.
The following Examples which should not be construed as constituting a limitation thereto are provided to illustrate the invention.